This information is intended for use by health professionals

1. Name of the medicinal product

Aprinox Tablets 2.5 mg

Bendroflumethiazide 2.5 mg Tablets

Aprinox Tablets 5 mg

Bendroflumethiazide 5 mg Tablets

2. Qualitative and quantitative composition

Each Aprinox Tablet 2.5 mg contains bendroflumethiazide 2.5 mg

Each Aprinox Tablet 5 mg contains bendroflumethiazide 5 mg

For excipients, see section 6.1

3. Pharmaceutical form

White tablets

4. Clinical particulars
4.1 Therapeutic indications

For the treatment of oedema and hypertension. Aprinox may also be used to suppress lactation.

4.2 Posology and method of administration

For oral administration.

Adults:

Oedema

Initially, 5-10 mg in the morning, daily or on alternate days; maintenance dose 5-10 mg one to three times weekly.

Hypertension

The usual dose is 2.5 mg taken in the morning. Higher doses are rarely necessary.

Suppression of lactation

5 mg in the morning and 5 mg at midday for about five days.

Children: Dosage in children may be up to 400 mcg/kg bodyweight initially, reducing to 50-100 mcg/kg bodyweight daily for maintenance.

Elderly: The dosage of thiazide diuretics may need to be reduced in the elderly, particularly when renal function is impaired, because of the possibility of electrolyte imbalance.

4.3 Contraindications

Aprinox is contra-indicated in patients with known hypersensitivity to thiazides; refractory hypokalaemia, hyponatraemia, hypercalcaemia; severe renal and hepatic impairment; symptomatic hyperuricaemia and Addison's disease.

4.4 Special warnings and precautions for use

Bendroflumethiazide should be used with caution in patients with mild to moderate hepatic or renal impairment (avoid if severe). Renal function should be continuously monitored during thiazide therapy. Thiazide diuretics may exacerbate or activate systemic lupus erythematosus in susceptible patients.

All thiazide diuretics can produce a degree of electrolyte imbalance, especially in patients with renal or hepatic impairment or when dosage is high or prolonged. Serum electrolytes should be checked for abnormalities, particularly hypokalaemia, and the latter corrected by the addition of a potassium supplement to the regimen. Aggravates diabetes and gout; increased risk of hypomagnesaemia in alcoholic cirrhosis.

Regular ongoing monitoring and blood tests are to be performed in elderly patients and patients who are on long term treatment with bendroflumethiazide.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Sensitivity to digitalis glycosides may be increased by the hypokalaemic effect of concurrent bendroflumethiazide. Patients should be observed for signs of digitalis intoxication, in particular arrhythmias, and if these appear, the dosage of the digitalis glycoside should be temporarily reduced and a potassium supplement given to restore stability.

Serum lithium concentrations may be increased by concurrent use of thiazide diuretics.

Non-steroidal anti-inflammatory agents may blunt the diuretic and antihypertensive effects of thiazide diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs.

Xanthines, beta-agonists, ACTH, corticosteroids, acetazolamide and carbenoxolone may exacerbate the hypokalaemia associated with thiazide use. Thiazide diuretics may enhance the neuromuscular blocking effects of the non-depolarising muscle relaxants, e.g. tubocurarine.

Thiazides may enhance the effects of antihypertensive agents, while postural hypotension associated with therapy may be enhanced by concomitant ingestion of alcohol, barbiturates or opioids.

Concomitant use of carbamazepine may increase the risk of hyponatraemia.

There is an increased risk of hyponatraemia if thiazides are given with amphotericin.

The risk of hypercalcaemia is increased by the concomitant intake of calcium salts or vitamin D preparations.

Concomitant use with cisplatin can lead to an increased risk of nephrotoxicity and ototoxicity.

The cardiac toxicity of disopyramide, amiodarone, flecainide and quinidine is increased if hypokalaemia occurs. The action of lidocaine and mexiletine is antagonised by hypokalaemia.

There is an increased risk of hyponatraemia when thiazides are used concomitantly with aminoglutethimide. Thiazides can cause an increased risk of hypercalcaemia with toremifene.

Colestipol and colestyramine may reduce the absorption of thiazide diuretics and should therefore be given 2 hours prior to, or after the ingestion of bendroflumethiazide.

Calcium-channel blockers and moxisylyte can cause an enhanced hypotensive effect.

There is an increased risk of postural hypotension with tricyclic antidepressants. There may also be an increased risk of hypokalaemia if thiazides are given with reboxetine. Concomitant use with monoamine oxidase inhibitors (MAOIs), baclofen or tizanidine may also give an increased hypotensive effect.

Oestrogens and combined oral contraceptives may antagonise the diuretic effect of thiazides.

There is an increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin.

Hypokalaemia increases the risk of ventricular arrhythmias with pimozide or thioridazine, therefore, concomitant use should be avoided. Hypokalaemia or other electrolyte imbalance also increases the risk of ventricular arrhythmias with terfenadine.

Bendroflumethiazide may interfere with a number of laboratory tests, including estimation of serum protein-bound iodine and tests of parathyroid function.

4.6 Pregnancy and lactation

Diuretics are best avoided for the management of oedema of pregnancy or hypertension in pregnancy as their use may be associated with hypokalaemia, increased blood viscosity and reduced placental perfusion.

There is inadequate evidence of safety in human pregnancy and foetal bone marrow depression and thrombocytopenia have been described. Foetal and neonatal jaundice have also been described.

As diuretics pass into breast milk and bendroflumethiazide can suppress lactation, its use should be avoided in mothers who wish to breast feed.

4.7 Effects on ability to drive and use machines

No adverse effects known.

4.8 Undesirable effects

All thiazide diuretics can produce a degree of electrolyte imbalance, e.g. hypokalaemia.

Thiazide diuretics may raise the serum uric acid levels with subsequent exacerbation of gout in susceptible subjects.

Thiazide diuretics sometimes lower carbohydrate tolerance and the insulin dosage of the diabetic patient may require adjustment. Care is necessary when bendroflumethiazide is administered to those with a known predisposition to diabetes.

Postural hypotension, mild gastro-intestinal effects and diarrhoea; hypokalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hypochloraemic alkalosis, hyperuricaemia, gout, hyperglycaemia, and altered plasma lipid concentration.

Less commonly, rashes, photosensitivity; blood disorders (including neutropenia and thrombocytopenia – when given in late pregnancy neonatal thrombocytopenia has been reported); pancreatitis, intrahepatic cholestasis, and hypersensitivity reactions (including pneumonitis, pulmonary oedema, severe skin reactions) also reported.

Rarely, blood dyscrasias, including agranulocytosis, aplastic anaemia, thrombocytopenia and leucopenia, and pancreatitis have been reported with long term therapy. Skin rashes and impotence (reversible on withdrawal of treatment) have occasionally been reported.

4.9 Overdose

Symptoms of overdosage include anorexia, nausea, vomiting, diarrhoea, diuresis, dehydration, hypotension, dizziness, weakness, muscle cramps, paraesthesia, tetany, gastrointestinal bleeding, hyponatraemia, hypo- or hyperglycaemia, hypokalaemia and metabolic alkalosis. Initial treatment consists of either emesis or gastric lavage, if appropriate. Otherwise treatment should be symptomatic and supportive including the correction of fluid and electrolyte imbalance.

Blood pressure should also be monitored.

There is no specific antidote.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Bendroflumethiazide is a thiazide diuretic which reduces the absorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. The excretion of other electrolytes, notably potassium and magnesium, is also increased. The excretion of calcium is reduced. Thiazides also reduce carbonic anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small and does not appreciably alter the acid base balance or the pH of the urine. Thiazides also have a hypotensive effect, due to a reduction in peripheral resistance and enhance the effects of other antihypertensive agents.

5.2 Pharmacokinetic properties

Bendroflumethiazide is completely absorbed from the gastrointestinal tract and it is fairly extensively metabolised. About 30% is excreted unchanged in the urine. The onset of diuretic action of the thiazides following oral administration occurs within two hours and the peak effect between three and six hours after administration. The duration of the diuretic action of bendroflumethiazide is between 18 and 24 hours. The onset of the hypotensive action is generally three or four days.

5.3 Preclinical safety data

Not applicable

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize Starch

Stearic acid

French chalk for tablets.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

None

6.5 Nature and contents of container

Amber glass bottle having a tin-plate cap with a waxed aluminium-faced pulpboard liner.

Pack size: 100 and 500 tablets.

PVC/Al blister pack

Pack size: 28 tablets

6.6 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

Waymade PLC Trading as Sovereign Medical

Sovereign House

Miles Gray Road

Basildon, Essex SS14 3FR

8. Marketing authorisation number(s)

Aprinox Tablets 2.5 mg: PL 06464/0706

Aprinox Tablets 5 mg: PL 06464/0707

9. Date of first authorisation/renewal of the authorisation

11 January 1999

10. Date of revision of the text

21/03/2013